Water exchange between human red blood cells and the plasma phase was measured by water proton nuclear magnetic resonance relaxation in the presence of low concentrations of Mn (II). The results were analyzed as a case of two-compartment exchange. The half-life of cell water was found to be 15 msec plus or minus 2 msec. The response of the cells to osmotic stress was measured, and the membrane permeability was found constant for shrunken cells, but increased with swelling. Freshly drawn human red cells in plasma show a 15-20 percent variation in permeability from subject to subject, and for most individuals, day to day variation. Red cells in an isotonic solution of HSA and NaCl give far more consistent results, and should be more suitable for experiments to detect abnormal response to osmotic stress in hereditary blood diseases. Relaxation of hemoglobin protons was measured, yielding information on interaction with hydration water.